| 研究実績の概要 |
This study aimed to unveil the regulation of immune-biased megakaryocytes (MKs) utilizing an immortalized MK cell line (imMKCLs). Expanding upon our discovery from last year, where we identified let-7a-5p and its downstream target gene RAS like proto-oncogene B (RALB) as potential key regulators involved in immune-skewed imMKCL development, in 2023, we further elucidated that the low activity of let-7a-5p leads to the upregulation of RALB expression, consequently activating activation of interferon-dependent signaling. Besides, our investigation extended to primary MKs revealed that RALB drives the immune-skewed transcriptional phenotypes of cord blood-derived MKs, thus shedding light on the regulation of human immune MKs.
In the context of ex vivo iPSC-platelet (iPSC-PLT) manufacturing, the dysregulation of immune properties/ subpopulations, along with the secretion of inflammatory cytokines, contributes to a decline in the quality of the entire imMKCL population. We propose that RALB could serve as a hallmark/predictor of imMKCL quality, thereby offering valuable insights into improving the standardization of iPSC-PLT generation for industrial-scale manufacturing. The study highlighted the significance of considering the immune/senescent attributes of donor cells and allogenic imMKCL master cell bank in future iPSC-PLT transfusion therapies, as they profoundly impact both the quantity and quality of the produced iPSC-PLTs. The work was published this year (Chen S.J. et al., Nature Communications, 2024).
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| 現在までの達成度 (区分) |
現在までの達成度 (区分)
2: おおむね順調に進展している
理由
In 2023, we successfully validated RALB as the determinant of immune-skewed MKs, a significant milestone in my research. I dedicated myself to organizing the findings and devising a strategy to prepare the paper for publication. I am pleased to report that the paper was accepted for publication after revision, making a major achievement for this project.
Besides, we made an unexpected discovery regarding new small compounds, RBC8 and Reparixin, which were found to improve the quality of imMKCL clones. Although these findings diverged from my original proposal, they hold promising potentially for future iPSC-PLT transfusion therapies. Despite the delay in completing task 3 due to the extensive efforts required for manuscript revision, the project run smoothly overall.
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| 今後の研究の推進方策 |
In 2024, my focus will shift towards to iPSCs of COVID-19 patients with varying disease severity, aiming to identify transcriptional differences between MKs derived from patients with varying disease severity. The iPSCs from COVID-19 patients has already been differentiated into MKs.
To achieve this goal, I plan to subject these samples to bulk RNA-seq analysis, and if necessary, scRNA-seq analysis will also be conducted. This comprehensive approach will enable us to gain deeper insights into the transcriptional profiles of MKs derived from COVID-19 patients, potentially uncovering crucial molecular signatures associated with disease severity.
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